1. Field of the Invention
This invention relates to a polyoxyalkylene derivative and a process of producing the same. More particularly, it relates to a polyoxyalkylene derivative useful for modification of biological substances, such as polypeptides, physiologically active proteins, enzymes, and modification of drug delivery systems (hereinafter DDS) such as liposomes and polymeric micelles.
2. Description of the Related Art
Terminal modified polyoxyalkylene compounds have recently been engaging attention as an important carrier for DDS. In particular, modification of polypeptides, physiologically active proteins, enzymes, etc. with a polyoxyalkylene compound and modification of liposomes, polymeric micelles, etc. with a polyoxyalkylene compound produce such effects as reduction of antigenicity (immunoreactivity), increase of drug stability, and prolongation of duration in the body. The terminal modified polyoxyalkylene compounds include those having a carboxyl group, an aldehyde group, an amino group, a thiol group, a maleimido group, etc. as a terminal functional group capable of reacting with a side chain functional group of peptides or proteins, such as the amino group of a lysine residue, the carboxyl group of an aspartic acid or glutamic acid residue, the thiol group of a cysteine residue, or with the amino group or the carboxyl group of phospholipids or polymeric micelle starting materials.
In particular, modification of the side chain thiol group of a cysteine residue or a thiol group introduced into a lysine residue with a maleimido-terminated polyoxyalkylene compound forms a thioether linkage, which is firmer than other linkages formed by other modification methods. Conventional polyoxyalkylene compounds having a maleimido end group used for the modification have been prepared by allowing polyethylene glycol or methoxypolyethylene glycol to react with an ester of N-hydroxysuccinimide and 6-maleimidocaproic acid, etc. However, these polyoxyalkylene compounds contain an ester linkage between the polyoxyalkylene chain and a maleimido group and are therefore easily hydrolyzed in the living body.
α-Maleimidoethyloxy-ω-methoxy(polyoxyalkylene), which is described in WO92/16221, WO98/3887, JP-A-12-191700, Proc. Natl. Acad. Sci. U.S.A., 97 (15) (2000), pp. 8543-8553, and Biochem. J., 351 (1) (2000), pp. 87-93, similarly has low storage stability.
Terminal modified polyoxyalkylene compounds for medical application must have few impurities of higher molecular weight than the desired compound, and a high degree of active group substitution. Therefore, terminal modified polyoxyalkylene compounds with a high GPC purity and a high degree of substitution with a terminal active group.
Synthetic Communications, 22 (16) (1992), pp. 2425-2429 reports a process of producing a maleimido group-terminated polyoxyalkylene derivative having a C2 alkyl group between the polyoxyalkylene chain and the maleimido group. The process reported cannot be seen as suited for industrial production because a large quantity of diethyl ether, which has a low ignition point, is used in purifying the intermediate.